The effect of anti-L-selectin (aselizumab) in multiple traumatized patients--results of a phase II clinical trial

OBJECTIVE: The objectives of this study were to evaluate safety (primary) and clinical efficacy (secondary) of the humanized monoclonal anti-L-selectin antibody aselizumab in severely injured patients. DESIGN: Prospective phase II, parallel group, double-blind, randomized, placebo-controlled clinical trial. SETTING: Fourteen medical intensive care units or trauma units in level I trauma centers in Belgium, Germany, and Poland. PATIENTS: Eighty-four patients with a sustained trauma due to a blunt or penetrating injury and a total Injury Severity Scale score of > or =25. INTERVENTIONS: Patients received either aselizumab at dosages of 0.5, 1, or 2 mg/kg or placebo within 6 hrs of the traumatic event and were followed for 6 wks. MEASUREMENTS AND MAIN RESULTS: The number of expeditable adverse events increased dose dependently over the aselizumab groups compared with placebo. There were no statistically significant differences between all groups regarding leukopenia and risk of infection. No immunologic response following infusion of aselizumab was noted. The number of patients with multiple organ failure, defined as a median value of the total Goris Multiple Organ Failure score of > or =5 on > or =2 consecutive days within 14 days, was not significantly different for the 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and placebo groups. There were no statistically significant differences in time of mechanical ventilation, length of stay in an intensive care unit, and total duration of hospitalization between treatment groups. CONCLUSIONS: Aselizumab was associated with a higher rate of infections and leucopenia; however, this difference was not significantly different compared with placebo. For all efficacy variables, aselizumab presented no significant trends but only a few scattered statistically significant differences between groups.     

Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia

Research has shown efficacy of melatonin treatment to advance sleep-wake rhythms in insomnia. In healthy adults, direction and magnitude of the phase shift depends on the timing of administration relative to the phase position of the circadian system. Therefore, in the present study we investigated whether in children with chronic sleep onset insomnia (SOI) efficacy of melatonin treatment in the early evening could be predicted from dim light melatonin onset (DLMO), a phase marker of the circadian system. We combined data of two previously published double blind, randomized, placebo-controlled trials in 110 participants, aged 6-12 years. Sleep was actigraphically estimated, and saliva collected, at baseline and in the third week of a 4-week treatment period with 5 mg melatonin or placebo at 18:00 or 19:00 hours. Primary outcome measures were pre- to post-treatment changes in dim light melatonin onset (DeltaDLMO), sleep onset (DeltaSO), sleep latency (DeltaSL), and total sleep duration (DeltaTSD). Melatonin advanced DLMO with +1:12 h (P < 0.001), SO with +0:42 h (P = 0.004), SL decreased with 25 min (P = 0.019), and TSD did not change significantly, as compared with placebo. In the melatonin-treated group, but not in the placebo-treated group, pretreatment DLMO was significantly related to DeltaDLMO [F(1, 29) = 7.28, P = 0.012] and DeltaSO [F(1, 25) = 7.72, P = 0.010]. The time interval between treatment administration and pretreatment DLMO (INT) was only significantly related to DeltaSO [F(1,26) = 5.40, P = 0.028]. The results suggest that in children with SOI, the efficacy of early evening melatonin to advance sleep onset and endogenous melatonin onset increases the later the pretreatment DLMO is.     

Pressure distribution patterns under the feet of new walkers: the first two months of independent walking

In order to describe foot function during the first weeks of independent walking, spatio-temporal pressure distribution patterns were measured. These data give detailed information about roll-off of the foot, by determining the course of the center of pressure, and about load bearing, by calculating relative vertical impulses under the feet. During those first weeks of independent walking, roll-off is very unstable. Although infants can occasionally perform a mature roll-off, a consistent pattern has not yet developed and there is instability. To improve stability the entire plantar surface area contributes to load bearing--first, because a larger contact area will improve stability, and second, because a forward shifting of the load allows more muscular control to compensate for minor imbalances under the foot.     

The association between postural alignment and psychosocial factors to upper quadrant pain in high school students: A prospective study

Prolonged sitting and psychosocial factors have been associated with musculoskeletal symptoms among adolescents. However, the impact of prolonged static sitting on musculoskeletal pain among South African high school students is uncertain. A prospective observational study was performed to determine whether sitting postural alignment and psychosocial factors contribute to the development of upper quadrant musculoskeletal pain (UQMP) in grade ten high school students working on desktop computers. The sitting postural alignment, depression, anxiety and computer use of 104 asymptomatic students were measured at baseline. At three and six months post baseline, the prevalence of UQMP was determined. Twenty-seven students developed UQMP due to seated or computer-related activities. An extreme cervical angle (<34.75° or >43.95°; OR 2.8; 95% CI: 1.1–7.3) and a combination of extreme cervical and thoracic angles (<63.1° or >71.1°; OR 2.2; 95% CI: 1.1–5.6) were significant postural risk factors for the development of UQMP. Boys with any extreme angle were more likely to suffer pain compared with boys with all middle range angles (OR 4.9; 95% CI: 1.0–24.5). No similar effect was found for girls. There was no strong relationship between depression, anxiety, computer exposure and UQMP among South African high school students.     

LRRK2 Quantification in Cerebrospinal Fluid of Patients with Parkinson's Disease and Atypical Parkinsonian Syndromes

Background

The alteration of leucine-rich repeat kinase 2 (LRRK2) kinase activity is thought to be involved in Parkinson's disease (PD) pathogenesis beyond familiar cases, and LRRK2 inhibitors are currently under investigation. Preliminary data suggest a relationship between LRRK2 alteration and cognitive impairment in PD.

Objective

To investigate cerebrospinal fluid (CSF) LRRK2 levels in PD and other parkinsonian disorders, also correlating them with cognitive impairment.

Methods

In this study, we retrospectively investigated by means of a novel highly sensitive immunoassay the levels of total and phosphorylated (pS1292) LRRK2 in CSF of cognitively unimpaired PD (n = 55), PD with mild cognitive impairment (n = 49), PD with dementia (n = 18), dementia with Lewy bodies (n = 12), atypical parkinsonian syndromes (n = 35), and neurological controls (n = 30).

Results

Total and pS1292 LRRK2 levels were significantly higher in PD with dementia with respect to PD with mild cognitive impairment and PD, and also showed a correlation with cognitive performances.

Conclusions

The tested immunoassay may represent a reliable method for assessing CSF LRRK2 levels. The results appear to confirm an association of LRRK2 alteration with cognitive impairment in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

New Therapy for Refractory Chronic Mechanical Low Back Pain—Restorative Neurostimulation to Activate the Lumbar Multifidus: One Year Results of a Prospective Multicenter Clinical Trial

Objectives

The purpose of the international multicenter prospective single arm clinical trial was to evaluate restorative neurostimulation eliciting episodic contraction of the lumbar multifidus for treatment of chronic mechanical low back pain (CMLBP) in patients who have failed conventional therapy and are not candidates for surgery or spinal cord stimulation (SCS).

Materials and Methods

Fifty‐three subjects were implanted with a neurostimulator (ReActiv8, Mainstay Medical Limited, Dublin, Ireland). Leads were positioned bilaterally with electrodes close to the medial branch of the L2 dorsal ramus nerve. The primary outcome measure was low back pain evaluated on a 10‐Point Numerical Rating Scale (NRS). Responders were defined as subjects with an improvement of at least the Minimal Clinically Important Difference (MCID) of ≥2‐point in low back pain NRS without a clinically meaningful increase in LBP medications at 90 days. Secondary outcome measures included Oswestry Disability Index (ODI) and Quality of Life (QoL; EQ‐5D).

Results

For 53 subjects with an average duration of CLBP of 14 years and average NRS of 7 and for whom no other therapies had provided satisfactory pain relief, the responder rate was 58%. The percentage of subjects at 90 days, six months, and one year with ≥MCID improvement in single day NRS was 63%, 61%, and 57%, respectively. Percentage of subjects with ≥MCID improvement in ODI was 52%, 57%, and 60% while those with ≥MCID improvement in EQ‐5D was 88%, 82%, and 81%. There were no unanticipated adverse events (AEs) or serious AEs related to the device, procedure, or therapy. The initial surgical approach led to a risk of lead fracture, which was mitigated by a modification to the surgical approach.

Conclusions

Electrical stimulation to elicit episodic lumbar multifidus contraction is a new treatment option for CMLBP. Results demonstrate clinically important, statistically significant, and lasting improvement in pain, disability, and QoL.